INSIGHTS INTO MITOCHONDRIAL DYSFUNCTION IN SPINAL AND BULBAR MUSCULAR ATROPHY THROUGH IPSC-DERIVED SKELETAL MUSCLE MODELS

Introduction: Spinal and bulbar muscular atrophy (SBMA), is a rare X-linked neuromuscular disorder caused by a CAG repeat expansion in the androgen receptor (AR) gene, producing a protein with an elongated poly Q tract (ARpolyQ)1. This mutation leads to progressive degeneration of lower motor neurons and skeletal muscle dysfunction. A growing number of evidence indicates that mitochondrial/metabolic dysfunction are critical points to disease progression2. This study aims to characterize mitochondrial abnormalities in skeletal muscle cells. Material & Methods: We differentiated induced pluripotent stem cell (iPSC)-derived from SBMA patients into skeletal muscle cells (SkMuCs)3, and used this model to investigate mitochondrial structure and function. Results: In SBMA myoblasts, mitochondria displayed alterations, appearing more rounded and smaller, which indicated fragmentation. They showed fewer branches per mitochondrion, suggesting an impaired mitochondrial network. Electron microscopy (EM) confirmed a reduced mitochondrial size in SBMA cells. Flowcytometry analysis assessment using JC-1 dye revealed a reduction in mitochondrial membrane potential. Furthermore, EM showed that SBMA cells has a diminished number and a smaller size of lipid droplets. Conclusion: Our findings demonstrate that SBMA muscle cells have significant mitochondrial defects, supporting mitochondrial dysfunction as a contributor to disease pathogenesis.These results support the use of patient-derived iPSC models for investigating disease mechanisms and potential therapeutic targets. Supported by: Kennedy’s Disease Association - USA (2018 grant to RC; 2020 grant to MG). Fondazione Cariplo - Italy (n. 2021 − 1544 to RC). Association Française contre les Myopathies - France (AFM Telethon n. 23236 to AP). PRIN—Progetti di ricerca di interesse nazionale (n. 2022EFLFL8 to AP).